ROLES OF HUMAN HEPATIC AND PULMONARY CYTOCHROME-P450 ENZYMES IN THE METABOLISM OF THE ENVIRONMENTAL CARCINOGEN 6-NITROCHYRSENE

6-Nitrochrysene is remarkably tumorigenic in the lung and liver of new born mice and approximates the activities of certain ultimate carcinog enic metabolites of polycyclic aromatic hydrocarbons. Previous studies have indicated that the major metabolic activation pathway of 6-nitro chrysene in newborn mice is initially through the formation of the pro ximate tumorigen trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene with subsequent formation of roxy-3,4-epoxy-1,2,3,4-tetrahydro-6-aminochrys ene. In order to provide information on the possible risk associated w ith human exposure to 6-nitrochrysene, the ability of human hepatic an d pulmonary microsomes to metabolize 6-nitrochrysene was investigated. The major metabolites identified in 11 hepatic microsomes were trans- 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, trans-9,10-dihydro-9,10-dih ydroxy-6-nitrochrysene, trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysen e, 6-aminochrysene, and chrysene-5,6-quinone. Following the incubation s of 6-nitrochrysene with 11 different human pulmonary microsomes, qua litatively similar metabolic patterns were obtained, although quantita tive differences were evident. These results demonstrated that human l iver and lung are capable of metabolizing 6-nitrochrysene to known pot ent carcinogenic metabolites via ring oxidation and nitroreduction. In an attempt to define the roles of individual human hepatic P450 invol ved in the metabolism of 6-nitrochrysene, the catalytic activities kno wn to be associated with a specific P450 were analyzed and compared wi th the levels of each metabolite of 6-nitrochrysene formed with the sa me microsomes. Rates of phenacetin O-deethylation (P450 1A2) and nifed ipine oxidation (P450 3A4) were well correlated with the rates of form ation of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminoch rysene, respectively. Inhibition studies with specific P450 inhibitors and antibodies further support the view that P450 1A2 and P450 3A4 ar e the major forms responsible for the formation of trans-1,2-dihydro-1 ,2-dihydroxy-6-nitrochrysene and 6-aminochrysene, respectively, in hum an liver. Further metabolism of trans-1,2-dihydro-1,2-dihydroxy-6-nitr ochrysene appears to require P450 3A4. In the human lung, P450 1A1 app ears to play a major role in the metabolism of 6-nitrochrysene to tran s-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene. These results provide som e requisite knowledge for evaluating human susceptibility to 6-nitroch rysene.